This is a revised application for competitive renewal of a grant aimed at identifying the genetic basis of severe bipolar disorder (BP-I), also termed manic depressive illness. The project aims to identify the full spectrum of genetic risk for BP-I in an isolated population that is exceptionally informative for genetic study, that of the Central Valley of Costa Rica (CVCR). The subjects include members of extended pedigrees, each with many individuals affected with BP-I. These pedigrees are hypothesized to segregate susceptibility alleles of relative high penetrance. Previous genome-wide linkage studies of two of these pedigrees have suggested localizations for such alleles on chromosomes 18q and 5q. In addition, a sample of BP-I probands, ascertained independently of each other, has been recruited from CVCR hospitals; this sample is most useful to identify susceptibility alleles of relatively low penetrance. Genome-wide linkage disequilibrium (LD) mapping studies of this sample have suggested several localizations of BP-I susceptibility alleles. In the renewal of this grant, further genotyping studies will be carried out. These studies will include both fine-scale mapping studies in genome regions suggested to contain BP-I genes by the prior genotyping studies in the CVCR, and independent genome-wide screens in newly ascertained pedigrees and population samples. The genotyping studies will delineate candidate regions for identifying BP-I genes.Much improvement is needed in the statistical and laboratory methodology for identifying genes for complex traits such as BP. Developing such improved methodology has been a major emphasis of this grant in the past and will still be a focus in the renewal; in particular, substantial effort is devoted to genetic mapping approaches that are specific to population isolates.